Abstract:

Claims:

1. A deuterium-enriched compound of formula I or a pharmaceutically
acceptable salt thereof: ##STR00030## wherein R1-R40 are
independently selected from H and D; andthe abundance of deuterium in
R1-R40 is at least 3%.

2. A deuterium-enriched compound of claim 1, wherein the abundance of
deuterium in R1-R40 is selected from at least 3%, at least 5%,
at least 10%, at least 15%, at least 20%, at least 25%, at least 30%, at
least 35%, at least 40%, at least 45%, at least 50%, at least 55%, at
least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at
least 85%, at least 90%, at least 95%, and 100%.

3. A deuterium-enriched compound of claim 1, wherein the abundance of
deuterium in R1-R4 is selected from at least 25%, at least 50%, at
least 75%, and 100%.

4. A deuterium-enriched compound of claim 1, wherein the abundance of
deuterium in R40 and R3-R6 is selected from at least 20%,
at least 40%, at least 60%, at least 80%, and 100%.

5. A deuterium-enriched compound of claim 1, wherein the abundance of
deuterium in R7-R8 is selected from at least 50% and 100%.

6. A deuterium-enriched compound of claim 1, wherein the abundance of
deuterium in R9-R11 and R22-R28 is selected from at
least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at
least 60%, at least 70%, at least 80%, at least 90%, and 100%.

7. A deuterium-enriched compound of claim 1, wherein the abundance of
deuterium in R12-R14 is selected from at least 33%, at least
67%, and 100%.

8. A deuterium-enriched compound of claim 1, wherein the abundance of
deuterium in R15-R18 is selected from at least 25%, at least
50%, at least 75%, and 100%.

9. A deuterium-enriched compound of claim 1, wherein the abundance of
deuterium in R19-R21 is selected from at least 33%, at least
67%, and 100%.

10. A deuterium-enriched compound of claim 1, wherein the abundance of
deuterium in R29-R30 is selected from at least 50% and 100%.

11. A deuterium-enriched compound of claim 1, wherein the abundance of
deuterium in R31-R33 is selected from at least 33%, at least
67%, and 100%.

12. A deuterium-enriched compound of claim 1, wherein the abundance of
deuterium in R34-R36 is selected from at least 33%, at least
67%, and 100%.

13. A deuterium-enriched compound of claim 1, wherein the abundance of
deuterium in R37-R39 is selected from at least 33%, at least
67%, and 100%.

14. A deuterium-enriched compound of claim 1, wherein the compound is
selected from compounds 1-12 of Table 1.

15. A deuterium-enriched compound of claim 1, wherein the compound is
selected from compounds 13-24 of Table 2.

16. An isolated deuterium-enriched compound of formula I or a
pharmaceutically acceptable salt thereof: ##STR00031## wherein
R1-R40 are independently selected from H and D; andthe
abundance of deuterium in R1-R40 is at least 3%.

17. An isolated deuterium-enriched compound of claim 16, wherein the
compound is selected from compounds 1-12 of Table 1.

18. An isolated deuterium-enriched compound of claim 16, wherein the
compound is selected from compounds 13-24 of Table 2.

19. A mixture of deuterium-enriched compounds of formula I or a
pharmaceutically acceptable salt thereof: ##STR00032## wherein
R1-R40 are independently selected from H and D; andthe
abundance of deuterium in R1-R40 is at least 3%.

20. A mixture of deuterium-enriched compound of claim 16, wherein the
compound is selected from compounds 1-12 of Table 1.

21. A mixture of deuterium-enriched compound of claim 16, wherein the
compound is selected from compounds 13-24 of Table 2.

22. A pharmaceutical composition, comprising: a pharmaceutically
acceptable carrier and a therapeutically effective amount of a compound
of claim 1 or a pharmaceutically acceptable salt form thereof.

23. A method for treating cancer comprising: administering, to a patient
in need thereof, a therapeutically effective amount of a compound of
claim 1 or a pharmaceutically acceptable salt form thereof.

[0002]This invention relates generally to deuterium-enriched trabectedin,
pharmaceutical compositions containing the same, and methods of using the
same.

BACKGROUND OF THE INVENTION

[0003]Trabectedin, shown below, is a well known tetrahydroisoquinoline
alkaloid

##STR00001##

Since trabectedin is a known and useful pharmaceutical, it is desirable to
discover novel derivatives thereof. Trabectedin is described in U.S. Pat.
No. 7,241,892; the contents of which are incorporated herein by
reference.

SUMMARY OF THE INVENTION

[0004]Accordingly, one object of the present invention is to provide
deuterium-enriched trabectedin or a pharmaceutically acceptable salt
thereof.

[0005]It is another object of the present invention to provide
pharmaceutical compositions comprising a pharmaceutically acceptable
carrier and a therapeutically effective amount of at least one of the
deuterium-enriched compounds of the present invention or a
pharmaceutically acceptable salt thereof.

[0006]It is another object of the present invention to provide a method
for treating cancer, comprising administering to a host in need of such
treatment a therapeutically effective amount of at least one of the
deuterium-enriched compounds of the present invention or a
pharmaceutically acceptable salt thereof.

[0007]It is another object of the present invention to provide a novel
deuterium-enriched trabectedin or a pharmaceutically acceptable salt
thereof for use in therapy.

[0008]It is another object of the present invention to provide the use of
a novel deuterium-enriched trabectedin or a pharmaceutically acceptable
salt thereof for the manufacture of a medicament (e.g., for the treatment
of cancer).

[0009]These and other objects, which will become apparent during the
following detailed description, have been achieved by the inventor's
discovery of the presently claimed deuterium-enriched trabectedin.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

[0010]Deuterium (D or 2H) is a stable, non-radioactive isotope of
hydrogen and has an atomic weight of 2.0144. Hydrogen naturally occurs as
a mixture of the isotopes 1H (hydrogen or protium), D (2H or
deuterium), and T (3H or tritium). The natural abundance of
deuterium is 0.015%. One of ordinary skill in the art recognizes that in
all chemical compounds with a H atom, the H atom actually represents a
mixture of H and D, with about 0.015% being D. Thus, compounds with a
level of deuterium that has been enriched to be greater than its natural
abundance of 0.015%, should be considered unnatural and, as a result,
novel over their non-enriched counterparts.

[0011]All percentages given for the amount of deuterium present are mole
percentages.

[0012]It can be quite difficult in the laboratory to achieve 100%
deuteration at any one site of a lab scale amount of compound (e.g.,
milligram or greater). When 100% deuteration is recited or a deuterium
atom is specifically shown in a structure, it is assumed that a small
percentage of hydrogen may still be present. Deuterium-enriched can be
achieved by either exchanging protons with deuterium or by synthesizing
the molecule with enriched starting materials.

[0013]The present invention provides deuterium-enriched trabectedin or a
pharmaceutically acceptable salt thereof There are forty hydrogen atoms
in the trabectedin portion of trabectedin as show by variables
R1-R40 in formula I below.

##STR00002##

[0014]The hydrogens present on trabectedin have different capacities for
exchange with deuterium. Hydrogen atoms R1-R4 are easily
exchangeable under physiological conditions and, if replaced by deuterium
atoms, it is expected that they will readily exchange for protons after
administration to a patient. The remaining hydrogen atoms are not easily
exchangeable for deuterium atoms. However, deuterium atoms at the
remaining positions may be incorporated by the use of deuterated starting
materials or intermediates during the construction of trabectedin.

[0015]The present invention is based on increasing the amount of deuterium
present in trabectedin above its natural abundance. This increasing is
called enrichment or deuterium-enrichment. If not specifically noted, the
percentage of enrichment refers to the percentage of deuterium present in
the compound, mixture of compounds, or composition. Examples of the
amount of enrichment include from about 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9,
10, 12, 16, 21, 25, 29, 33, 37, 42, 46, 50, 54, 58, 63, 67, 71, 75, 79,
84, 88, 92, 96, to about 100 mol %. Since there are 40 hydrogens in
trabectedin, replacement of a single hydrogen atom with deuterium would
result in a molecule with about 3% deuterium enrichment. In order to
achieve enrichment less than about 3%, but above the natural abundance,
only partial deuteration of one site is required. Thus, less than about
3% enrichment would still refer to deuterium-enriched trabectedin.

[0016]With the natural abundance of deuterium being 0.015%, one would
expect that for approximately every 6,667 molecules of trabectedin
(1/0.00015=6,667), there is one naturally occurring molecule with one
deuterium present. Since trabectedin has 40 positions, one would roughly
expect that for approximately every 266,680 molecules of trabectedin
(40×6,667), all 40 different, naturally occurring, mono-deuterated
trabectedins would be present. This approximation is a rough estimate as
it doesn't take into account the different exchange rates of the hydrogen
atoms on trabectedin. For naturally occurring molecules with more than
one deuterium, the numbers become vastly larger. In view of this natural
abundance, the present invention, in an embodiment, relates to an amount
of an deuterium enriched compound, whereby the enrichment recited will be
more than naturally occurring deuterated molecules.

[0017]In view of the natural abundance of deuterium-enriched trabectedin,
the present invention also relates to isolated or purified
deuterium-enriched trabectedin. The isolated or purified
deuterium-enriched trabectedin is a group of molecules whose deuterium
levels are above the naturally occurring levels (e.g., 3%). The isolated
or purified deuterium-enriched trabectedin can be obtained by techniques
known to those of skill in the art (e.g., see the syntheses described
below).

[0018]The present invention also relates to compositions comprising
deuterium-enriched trabectedin. The compositions require the presence of
deuterium-enriched trabectedin which is greater than its natural
abundance. For example, the compositions of the present invention can
comprise (a) a μg of a deuterium-enriched trabectedin; (b) a mg of a
deuterium-enriched trabectedin; and, (c) a gram of a deuterium-enriched
trabectedin.

[0019]In an embodiment, the present invention provides an amount of a
novel deuterium-enriched trabectedin.

[0020]Examples of amounts include, but are not limited to (a) at least
0.01, 0.02, 0.03, 0.04, 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, to 1 mole, (b) at
least 0.1 moles, and (c) at least 1 mole of the compound. The present
amounts also cover lab-scale (e.g., gram scale), kilo-lab scale (e.g.,
kilogram scale), and industrial or commercial scale (e.g., multi-kilogram
or above scale) quantities as these will be more useful in the actual
manufacture of a pharmaceutical. Industrial/commercial scale refers to
the amount of product that would be produced in a batch that was designed
for clinical testing, formulation, sale/distribution to the public, etc.

[0021]In another embodiment, the present invention provides a novel,
deuterium enriched compound of formula I or a pharmaceutically acceptable
salt thereof.

##STR00003##

[0022]wherein R1-R40 are independently selected from H and D;
and the abundance of deuterium in R1-R40 is at least 3%. The
abundance can also be (a) at least 5%, (b) at least 10%, (c) at least
15%, (d) at least 20%, (e) at least 25%, (f) at least 30%, (g) at least
35%, (h) at least 40%, (i) at least 45%, (j) at least 50%, (k) at least
55%, (l) at least 60%, (m) at least 65%, (n) at least 70%, (o) at least
75%, (p) at least 80%, (q) at least 85%, (r) at least 90%, (s) at least
95%, and (t) 100%.

[0023]In another embodiment, the present invention provides a novel,
deuterium enriched compound of formula I or a pharmaceutically acceptable
salt thereof, wherein the abundance of deuterium in R1-R4 is at
least 25%. The abundance can also be (a) at least 50%, (b) at least 75%,
and (c) 100%.

[0024]In another embodiment, the present invention provides a novel,
deuterium enriched compound of formula I or a pharmaceutically acceptable
salt thereof, wherein the abundance of deuterium in R40
R3-R6 is at least 20%. The abundance can also be (a) at least
40%, (b) at least 60%, (c) at least 80%, and (d) 100%.

[0025]In another embodiment, the present invention provides a novel,
deuterium enriched compound of formula I or a pharmaceutically acceptable
salt thereof, wherein the abundance of deuterium in R7-R8 is at
least 50%. The abundance can also be (a) 100%.

[0026]In another embodiment, the present invention provides a novel,
deuterium enriched compound of formula I or a pharmaceutically acceptable
salt thereof, wherein the abundance of deuterium in R9-R11 and
R22-R28 is at least 10%. The abundance can also be (a) at least
20%, (b) at least 30%, (c) at least 40%, (d) at least 50%, (e) at least
60%, (f) at least 70%, (g) at least 80%, (h) at least 90%, and (i) 100%.

[0027]In another embodiment, the present invention provides a novel,
deuterium enriched compound of formula I or a pharmaceutically acceptable
salt thereof, wherein the abundance of deuterium in R12-R14 is
at least 33%. The abundance can also be (a) at least 67%, and (b) 100%.

[0028]In another embodiment, the present invention provides a novel,
deuterium enriched compound of formula I or a pharmaceutically acceptable
salt thereof, wherein the abundance of deuterium in R15-R18 is
at least 25%. The abundance can also be (a) at least 50%, (b) at least
75%, and (c) 100%.

[0029]In another embodiment, the present invention provides a novel,
deuterium enriched compound of formula I or a pharmaceutically acceptable
salt thereof, wherein the abundance of deuterium in R19-R21 is
at least 33%. The abundance can also be (a) at least 67%, and (b) 100%.

[0030]In another embodiment, the present invention provides a novel,
deuterium enriched compound of formula I or a pharmaceutically acceptable
salt thereof, wherein the abundance of deuterium in R29-R30 is
at least 50%. The abundance can also be (a) 100%.

[0031]In another embodiment, the present invention provides a novel,
deuterium enriched compound of formula I or a pharmaceutically acceptable
salt thereof, wherein the abundance of deuterium in R31-R33 is
at least 33%. The abundance can also be (a) at least 67%, and (b) 100%.

[0032]In another embodiment, the present invention provides a novel,
deuterium enriched compound of formula I or a pharmaceutically acceptable
salt thereof, wherein the abundance of deuterium in R34-R36 is
at least 33%. The abundance can also be (a) at least 67%, and (b) 100%.

[0033]In another embodiment, the present invention provides a novel,
deuterium enriched compound of formula I or a pharmaceutically acceptable
salt thereof, wherein the abundance of deuterium in R37-R39 is
at least 33%. The abundance can also be (a) at least 67%, and (b) 100%.

[0034]In another embodiment, the present invention provides an isolated
novel, deuterium enriched compound of formula I or a pharmaceutically
acceptable salt thereof.

##STR00004##

[0035]wherein R1-R40 are independently selected from H and D;
and the abundance of deuterium in R1-R40 is at least 3%. The
abundance can also be (a) at least 5%, (b) at least 10%, (c) at least
15%, (d) at least 20%, (e) at least 25%, (f) at least 30%, (g) at least
35%, (h) at least 40%, (i) at least 45%, (j) at least 50%, (k) at least
55%, (l) at least 60%, (m) at least 65%, (n) at least 70%, (o) at least
75%, (p) at least 80%, (q) at least 85%, (r) at least 90%, (s) at least
95%, and (t) 100%.

[0036]In another embodiment, the present invention provides an isolated
novel, deuterium enriched compound of formula I or a pharmaceutically
acceptable salt thereof, wherein the abundance of deuterium in
R1-R4 is at least 25%. The abundance can also be (a) at least
50%, (b) at least 75%, and (c) 100%.

[0037]In another embodiment, the present invention provides an isolated
novel, deuterium enriched compound of formula I or a pharmaceutically
acceptable salt thereof, wherein the abundance of deuterium in R40
R3-R6 is at least 20%. The abundance can also be (a) at least
40%, (b) at least 60%, (c) at least 80%, and (d) 100%.

[0038]In another embodiment, the present invention provides an isolated
novel, deuterium enriched compound of formula I or a pharmaceutically
acceptable salt thereof, wherein the abundance of deuterium in
R7-R8 is at least 50%. The abundance can also be (a) 100%.

[0039]In another embodiment, the present invention provides an isolated
novel, deuterium enriched compound of formula I or a pharmaceutically
acceptable salt thereof, wherein the abundance of deuterium in
R9-R11 and R22-R28 is at least 10%. The abundance can
also be (a) at least 20%, (b) at least 30%, (c) at least 40%, (d) at
least 50%, (e) at least 60%, (f) at least 70%, (g) at least 80%, (h) at
least 90%, and (i) 100%.

[0040]In another embodiment, the present invention provides an isolated
novel, deuterium enriched compound of formula I or a pharmaceutically
acceptable salt thereof, wherein the abundance of deuterium in
R12-R14 is at least 33%. The abundance can also be (a) at least
67%, and (b) 100%.

[0041]In another embodiment, the present invention provides an isolated
novel, deuterium enriched compound of formula I or a pharmaceutically
acceptable salt thereof, wherein the abundance of deuterium in
R15-R18 is at least 25%. The abundance can also be (a) at least
50%, (b) at least 75%, and (c) 100%.

[0042]In another embodiment, the present invention provides an isolated
novel, deuterium enriched compound of formula I or a pharmaceutically
acceptable salt thereof, wherein the abundance of deuterium in
R19-R21 is at least 33%. The abundance can also be (a) at least
67%, and (b) 100%.

[0043]In another embodiment, the present invention provides an isolated
novel, deuterium enriched compound of formula I or a pharmaceutically
acceptable salt thereof, wherein the abundance of deuterium in
R29-R30 is at least 50%. The abundance can also be (a) 100%.

[0044]In another embodiment, the present invention provides an isolated
novel, deuterium enriched compound of formula I or a pharmaceutically
acceptable salt thereof, wherein the abundance of deuterium in
R31-R33 is at least 33%. The abundance can also be (a) at least
67%, and (b) 100%.

[0045]In another embodiment, the present invention provides an isolated
novel, deuterium enriched compound of formula I or a pharmaceutically
acceptable salt thereof, wherein the abundance of deuterium in
R34-R36 is at least 33%. The abundance can also be (a) at least
67%, and (b) 100%.

[0046]In another embodiment, the present invention provides an isolated
novel, deuterium enriched compound of formula I or a pharmaceutically
acceptable salt thereof, wherein the abundance of deuterium in
R37-R39 is at least 33%. The abundance can also be (a) at least
67%, and (b) 100%.

[0047]In another embodiment, the present invention provides novel mixture
of deuterium enriched compounds of formula I or a pharmaceutically
acceptable salt thereof.

##STR00005##

[0048]wherein R1-R40 are independently selected from H and D;
and the abundance of deuterium in R1-R40 is at least 3%. The
abundance can also be (a) at least 5%, (b) at least 10%, (c) at least
15%, (d) at least 20%, (e) at least 25%, (f) at least 30%, (g) at least
35%, (h) at least 40%, (i) at least 45%, (j) at least 50%, (k) at least
55%, (l) at least 60%, (m) at least 65%, (n) at least 70%, (o) at least
75%, (p) at least 80%, (q) at least 85%, (r) at least 90%, (s) at least
95%, and (t) 100%.

[0049]In another embodiment, the present invention provides an isolated
novel, deuterium enriched compound of formula I or a pharmaceutically
acceptable salt thereof, wherein the abundance of deuterium in
R1-R4 is at least 25%. The abundance can also be (a) at least
50%, (b) at least 75%, and (c) 100%.

[0050]In another embodiment, the present invention provides an isolated
novel, deuterium enriched compound of formula I or a pharmaceutically
acceptable salt thereof, wherein the abundance of deuterium in R40
R3-R6 is at least 20%. The abundance can also be (a) at least
40%, (b) at least 60%, (c) at least 80%, and (d) 100%.

[0051]In another embodiment, the present invention provides an isolated
novel, deuterium enriched compound of formula I or a pharmaceutically
acceptable salt thereof, wherein the abundance of deuterium in
R7-R8 is at least 50%. The abundance can also be (a) 100%.

[0052]In another embodiment, the present invention provides an isolated
novel, deuterium enriched compound of formula I or a pharmaceutically
acceptable salt thereof, wherein the abundance of deuterium in
R9-R11 and R22-R28 is at least 10%. The abundance can
also be (a) at least 20%, (b) at least 30%, (c) at least 40%, (d) at
least 50%, (e) at least 60%, (f) at least 70%, (g) at least 80%, (h) at
least 90%, and (i) 100%.

[0053]In another embodiment, the present invention provides an isolated
novel, deuterium enriched compound of formula I or a pharmaceutically
acceptable salt thereof, wherein the abundance of deuterium in
R12-R14 is at least 33%. The abundance can also be (a) at least
67%, and (b) 100%.

[0054]In another embodiment, the present invention provides an isolated
novel, deuterium enriched compound of formula I or a pharmaceutically
acceptable salt thereof, wherein the abundance of deuterium in
R15-R18 is at least 25%. The abundance can also be (a) at least
50%, (b) at least 75%, and (c) 100%.

[0055]In another embodiment, the present invention provides an isolated
novel, deuterium enriched compound of formula I or a pharmaceutically
acceptable salt thereof, wherein the abundance of deuterium in
R19-R21 is at least 33%. The abundance can also be (a) at least
67%, and (b) 100%.

[0056]In another embodiment, the present invention provides an isolated
novel, deuterium enriched compound of formula I or a pharmaceutically
acceptable salt thereof, wherein the abundance of deuterium in
R29-R30 is at least 50%. The abundance can also be (a) 100%.

[0057]In another embodiment, the present invention provides an isolated
novel, deuterium enriched compound of formula I or a pharmaceutically
acceptable salt thereof, wherein the abundance of deuterium in
R31-R33 is at least 33%. The abundance can also be (a) at least
67%, and (b) 100%.

[0058]In another embodiment, the present invention provides an isolated
novel, deuterium enriched compound of formula I or a pharmaceutically
acceptable salt thereof, wherein the abundance of deuterium in
R34-R36 is at least 33%. The abundance can also be (a) at least
67%, and (b) 100%.

[0059]In another embodiment, the present invention provides an isolated
novel, deuterium enriched compound of formula I or a pharmaceutically
acceptable salt thereof, wherein the abundance of deuterium in
R37-R39 is at least 33%. The abundance can also be (a) at least
67%, and (b) 100%.

[0060]In another embodiment, the present invention provides novel
pharmaceutical compositions, comprising: a pharmaceutically acceptable
carrier and a therapeutically effective amount of a deuterium-enriched
compound of the present invention.

[0061]In another embodiment, the present invention provides a novel method
for treating cancer comprising: administering to a patient in need
thereof a therapeutically effective amount of a deuterium-enriched
compound of the present invention.

[0062]In another embodiment, the present invention provides an amount of a
deuterium-enriched compound of the present invention as described above
for use in therapy.

[0063]In another embodiment, the present invention provides the use of an
amount of a deuterium-enriched compound of the present invention for the
manufacture of a medicament (e.g., for the treatment of cancer).

[0064]The present invention may be embodied in other specific forms
without departing from the spirit or essential attributes thereof. This
invention encompasses all combinations of preferred aspects of the
invention noted herein. It is understood that any and all embodiments of
the present invention may be taken in conjunction with any other
embodiment or embodiments to describe additional more preferred
embodiments. It is also to be understood that each individual element of
the preferred embodiments is intended to be taken individually as its own
independent preferred embodiment. Furthermore, any element of an
embodiment is meant to be combined with any and all other elements from
any embodiment to describe an additional embodiment.

Definitions

[0065]The examples provided in the definitions present in this application
are non-inclusive unless otherwise stated. They include but are not
limited to the recited examples.

[0066]The compounds of the present invention may have asymmetric centers.
Compounds of the present invention containing an asymmetrically
substituted atom may be isolated in optically active or racemic forms. It
is well known in the art how to prepare optically active forms, such as
by resolution of racemic forms or by synthesis from optically active
starting materials. All processes used to prepare compounds of the
present invention and intermediates made therein are considered to be
part of the present invention. All tautomers of shown or described
compounds are also considered to be part of the present invention.

[0067]"Host" preferably refers to a human. It also includes other mammals
including the equine, porcine, bovine, feline, and canine families.

[0068]"Treating" or "treatment" covers the treatment of a disease-state in
a mammal, and includes: (a) preventing the disease-state from occurring
in a mammal, in particular, when such mammal is predisposed to the
disease-state but has not yet been diagnosed as having it; (b) inhibiting
the disease-state, e.g., arresting it development; and/or (c) relieving
the disease-state, e.g., causing regression of the disease state until a
desired endpoint is reached. Treating also includes the amelioration of a
symptom of a disease (e.g., lessen the pain or discomfort), wherein such
amelioration may or may not be directly affecting the disease (e.g.,
cause, transmission, expression, etc.).

[0069]"Therapeutically effective amount" includes an amount of a compound
of the present invention that is effective when administered alone or in
combination to treat the desired condition or disorder. "Therapeutically
effective amount" includes an amount of the combination of compounds
claimed that is effective to treat the desired condition or disorder. The
combination of compounds is preferably a synergistic combination.
Synergy, as described, for example, by Chou and Talalay, Adv. Enzyme
Regul. 1984, 22:27-55, occurs when the effect of the compounds when
administered in combination is greater than the additive effect of the
compounds when administered alone as a single agent. In general, a
synergistic effect is most clearly demonstrated at sub-optimal
concentrations of the compounds. Synergy can be in terms of lower
cytotoxicity, increased antiviral effect, or some other beneficial effect
of the combination compared with the individual components.

[0073]Numerous modifications and variations of the present invention are
possible in light of the above teachings. It is therefore to be
understood that within the scope of the appended claims, the invention
may be practiced otherwise that as specifically described herein.